1. Field of the Invention
This invention relates to novel heterocycle substituted imidazoles. The invention also relates to pharmaceutical compositions containing the novel imidazoles and pharmaceutical methods using them, alone and in conjugation with other drugs, especially diuretics, angiotensin converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDS).
The compounds of this invention inhibit the action of the hormone angiotensin-II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha.2-globulin, angiotensinogen, to produce angiotensin-I, which is then converted by ACE to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure. Administration of a compound of this invention with a diuretic such as furosemide or hydrochlorothiazide, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound. Administration of a compound of this invention with a NSAID can prevent renal failure which sometimes results from administration of a NSAID.
Several peptide analogs of AII are known to inhibit the effects of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by their partial agonist activity and lack of oral absorption (M. Antonaccio, Clin. Exp. Hypertens., 1982, A4, 27-46; D. H. P. Streeten and G. H. Anderson, Jr.--Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed., A. E. Doyle, Vol. 5, pages 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).
Several non-peptide antagonists of AII have been disclosed. Some of these compounds are covered by U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804; in European Patent Applications 028,834; 324,377; 253,310; and 291,969; and in articles by A. T. Chiu, et al. (Eur. J. Pharm. Exp. Therap., 1988, 157, 13-21) and by P. C. Wong, et al. (J. Pharm. Exp. Therap. 1988, 247, 1-7).
These publications disclose substituted imidazole compounds which are bonded through a lower alkyl bridge to a substituted phenyl. Among the above references, European Patent Application 324,377 describes imidazoles where the imidazole ring can be substituted at the 4- or 5-position with heterocycle containing substituents, including ##STR2## --CH.dbd.CH(CH.sub.2).sub.0-5 COR.sup.16, --COR.sup.16, --(CH.sub.2).sub.0-5 -CH(CH.sub.3)--COR.sup.16 and --(CH.sub.2).sub.1-10 COR.sup.16, where R.sup.16 may be ##STR3## in which Q is OH, CH.sub.2 or NR.sup.20, where R.sup.20 is H, alkyl of 1 to 4 carbon atoms or phenyl.
US90/03683 describes imidazoles having the same basic formula as EPO 0324377, where the imidazole ring can be substituted at the 4- or 5-position with heterocycle containing substituents, including alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms substituted with N-phthalimido or ##STR4## --CH.dbd.CH(CH.sub.2).sub.0-5 COR.sup.16, --COR.sup.16, --(CH.sub.2).sub.0-5 -CH(CH.sub.3)--COR.sup.16 and --(CH.sub.2).sub.1-10 OCOR.sup.16 where R.sup.16 is as defined in EPO 0324377.
None of the above publications disclose the novel heterocycle substituted imidazoles of the present invention.